Grant E. O’Keefe

Plasma CD14 decreases monocyte responses to LPS by transferring cell-bound LPS to plasma lipoproteins

CD14, a myeloid cell-surface receptor and soluble plasma protein, binds LPS and other microbial molecules and initiates the innate immune response to bacterial invasion. The blood concentration of soluble CD14 (sCD14) increases during the systemic response to infection. Although high sCD14 blood levels have correlated with increased risk of dying from severe sepsis, sCD14 can diminish cell responses to LPS. We show here that in human serum, sCD14 increases the rate at which cell-bound LPS is released from the monocyte surface and binds to plasma lipoproteins. This enhanced rate of LPS efflux is associated with a significant reduction in the ability of monocytes to produce cytokines in response to LPS. Serum from septic patients reduced the LPS-monocyte interaction by as much as tenfold, and depletion of sCD14 from the serum restored LPS-monocyte binding and release kinetics to near normal levels. In serum from septic patients, monocyte-bound LPS also moved more rapidly into lipoproteins, which completely neutralized the biologic activity of the LPS that bound to them. In human plasma, sCD14 thus diminishes monocyte responses to LPS by transferring cell-bound LPS to lipoproteins. Stress-related increases in plasma sCD14 levels may help prevent inflammatory responses within the blood.

Regional and Systemic Cytokine Responses to Acute Inflammation of the Vermiform Appendix

ObjectiveTo measure local (peritoneal fluid) and systemic (plasma) cytokine profiles in patients with infection-inflammation of the vermiform appendix, a relatively mild, localized inflammatory process. Summary Background DataThe systemic host response to invading microorganisms, often termed the systemic inflammatory response syndrome (SIRS), includes changes in heart rate, respiratory rate, body temperature, and circulating white blood cell numbers. Although these changes can be induced experimentally by administering proinflammatory cytokines, the mediators that appear in the bloodstream during early, localized infection in humans have not been defined. MethodsThe authors studied 56 patients with pathologically proven appendicitis. Blood was obtained before the induction of anesthesia, when 82% of the patients met the criteria for SIRS. Peritoneal fluid (PF) was obtained by intraoperative lavage. Cytokines were measured by immunoassay. To assess the net impact of the mediators within plasma, the authors studied the ability of patient plasma to augment or suppress bacterial lipopolysaccharide (LPS) stimulation of monocytes in vitro. ResultsOf the proinflammatory cytokines, tumor necrosis factor-alpha was present in PF but not in plasma, interleukin (IL)-1&bgr; and interferon-&ggr; were found in low concentrations in both PF and plasma, and IL-12 (p70) was detectable in plasma but not PF. In contrast, IL-6 and IL-1 receptor antagonist (IL-1ra) were the most abundant cytokines in the PF and plasma, and the concentrations of IL-4 and IL-10 were also elevated in both compartments. Patients with more severe appendicitis had higher plasma levels of IL-6 and IL-10 and lower plasma levels of IL-12 and interferon-&ggr; than did those with uncomplicated disease. Patient plasma inhibited LPS-induced stimulation of a monocyte cell line, and this inhibition was accentuated by complicated disease. ConclusionsAs judged from the pattern of soluble cytokines in plasma and the effect of the plasma on monocyte activation by LPS, mild, localized infection can induce a systemic response that is predominantly anti-inflammatory.

Protein Delivery in the Intensive Care Unit: Optimal or Suboptimal?:

Emerging evidence suggests that exogenous protein/amino acid supplementation has the potential to improve the recovery of critically ill patients. After a careful review of the published evidence, experts have concluded that critically ill patients should receive up to 2.0–2.5 g/kg/d of protein. Despite this, however, recent review of current International Nutrition Survey data suggests that protein in critically ill patients is underprescribed and grossly underdelivered. Furthermore, the survey suggests that most of protein administration comes from enteral nutrition (EN) despite the availability of products and protocols that enhance the delivery of protein/amino acids in the intensive care unit (ICU) setting. While future research clarifies the dose, timing, and composition for exogenous protein administration, as well as identification of patients who will benefit the most, ongoing process improvement initiatives should target a concerted effort to increase protein intake in the critically ill. This assertion follows from the notion that current patients are possibly being harmed while we wait for confirmatory evidence. Further research should also develop better tools to enable bedside practitioners to monitor optimal or adequate protein intake for individual patients. Finally, exploring the effect of combining adequate protein delivery with early mobility and/or resistance exercise in the ICU setting has the greatest potential for improving the functional outcomes of survivors of critical illness and warrants further study.

The evolution of the diagnostic work-up for stab wounds to the back and flank

BACKGROUND Stab wounds to the back and flank infrequently cause injuries requiring operative treatment. Triple-contrast CT scan (3CT) has essentially replaced diagnostic peritoneal lavage (DPL) as the primary means of identifying patients who require operative intervention. This study aims to review the evolution of the diagnostic work-up for stab wounds to the back and flank. METHODS We performed a retrospective review of haemodynamically stable patients with stab wound to the back or flank treated at a single Level 1 trauma centre over a 10-year period. Diagnostic accuracy of DPL and 3CT screening tests were evaluated against the patients subsequent clinical course. The elapsed time between emergency department (ED) presentation and test results was recorded and compared. RESULTS A total of 177 patients were identified. 76 patients had stab wounds isolated to the back, 90 had stab wounds isolated to the flank and 11 had wounds in both locations. CT ultimately became the predominant initial diagnostic test during the study period. Although less frequently used over time, DPL retained good sensitivity and specificity for injuries requiring operative intervention (92% and 83%, respectively). 3CT identified all injuries requiring laparotomy (100% sensitivity) and had a specificity of 96%. 3CT was a more time-consuming process, with results available at a median of 3:31h after arrival to the ED, as compared to 1:03h for DPL (p<0.01). CONCLUSIONS 3CT diagnosed all injuries requiring operative intervention, and its use was associated with a lower rate of non-therapeutic laparotomies. However, average time to diagnosis by 3CT was prolonged compared to DPL. Although 3CT has become the predominant diagnostic test when evaluating patients with stab wounds to the back and flank at our institution, efforts to further expedite the diagnostic work-up are necessary.

Acoustic hemostasis: Underlying mechanisms

Cessation of hemorrhage using extrinsic, interventional methods is possible with delivery of energy to bleeding tissues, i.e., cauterization. High intensity focused ultrasound (HIFU) is one such method, with significant advantages of delivering high levels of energy to well‐defined regions of deep‐seated tissues, even during profuse bleeding. The physical mechanisms involved in this process include thermal and mechanical effects of HIFU, leading to various biological effects. Our results using HIFU devices of 1–5 MHz, and focal, derated intensities of 1,000–10,000 W/cm2, in solid organs such as liver, spleen, and kidneys and major and minor blood vessels, show that temperature of targeted tissues reaches 70–100°C within seconds, with formation of microbubbles, approximately 5−−200 μ in size, and concentration of 100 bubbles/mm3. It appears that boiling of interstitial fluids and blood and acoustic cavitation are both involved. The biological effects include coagulative necrosis, mechanical disruption of t...

Melanocortin-1 Receptor Polymorphisms and the Risk of Complicated Sepsis After Trauma: A Candidate Gene Association Study.

Objective: The aim of the study was to determine if melanocortin-1 receptor (MC1R) single nucleotide polymorphisms (SNPs) are associated with complicated sepsis after trauma. Background: Nosocomial infections are an important cause of morbidity and mortality after trauma. Several SNPs in inflammation-related genes have been associated with sepsis. MC1R is an anti-inflammatory mediator that may be involved in the immune response after trauma. Patients and Methods: We genotyped eight common MC1R SNPs in genomic DNA from subjects enrolled in a previously reported prospective cohort study. Subjects were adult trauma patients admitted to the intensive care unit at a Level 1 trauma center (2003–2005). Results: A total of 1,246 subjects were included in the analysis. The majority were male (70%), severely injured (81%), and injured by a blunt mechanism (89%). Forty percent developed sepsis, and 23% developed complicated sepsis, which was defined as sepsis with organ dysfunction. In logistic regression analysis, with adjustments for age, sex, body mass index, injury severity score, red blood cell transfusion requirement, and mechanism of injury, the MC1RR163Q variant (rs885479) was associated with a lower risk of developing complicated sepsis (adjusted odds ratio [ORadj] = 0.48, 95% confidence interval [CI]: 0.28–0.81, P = 0.006). In a subgroup of 511 subjects with genome-wide SNP data, the association between the MC1RR163Q variant and complicated sepsis remained significant after adjusting for genetic substructure (by principal components) and the above clinical factors (ORadj = 0.30, 95% CI: 0.13–0.70, P = 0.005). Conclusions: MC1RR163Q is associated with a lower risk of complicated sepsis after trauma. Therapeutic targeting of MC1R may be beneficial for trauma patients at risk for complicated sepsis.

Parenteral Nutrition Utilization After Implementation of Multidisciplinary Nutrition Support Team Oversight A Prospective Cohort Study

BACKGROUND Multidisciplinary nutrition teams can help guide the use of parenteral nutrition (PN), thereby reducing infectious risk, morbidity, and associated costs. Starting in 2007 at Harborview Medical Center, weekly multidisciplinary meetings were established to review all patients receiving PN. This study reports on observed changes in utilization from 2005-2010. MATERIALS AND METHODS All patients who received PN from 2005-2010 were followed prospectively. Clinical data and PN utilization data were recorded. Patients were grouped into cohorts based on exposure to weekly multidisciplinary nutrition team meetings (from 2005-2007 and from 2008-2010). Patients were also stratified by location, primary service, and ultimate disposition. RESULTS In total, 794 patients were included. After initiation of multidisciplinary nutrition meetings, the rate of patients who started PN decreased by 27% (relative risk [RR], 0.73; 95% confidence interval [CI], 0.63-0.84). A reduction in the number of patients receiving PN was observed in both the intensive care unit (ICU) and on the acute care floor (RR, 0.64; 95% CI, 0.53-0.77 and RR, 0.80; 95% CI, 0.64-0.99, respectively). The rate of patients with short-duration PN use (PN duration of <5 days) declined by 30% in the ICU (RR, 0.70; 95% CI, 0.51-0.97) and by 27% on acute care floors (RR, 0.73; 95% CI, 0.51-1.03). CONCLUSIONS Weekly multidisciplinary review of patients receiving PN was associated with reductions in the number of patients started on PN, total days that patients received PN, and number of patients who had short-duration (<5 days) PN use.

HIFU Hemostasis of Liver Injuries Enhanced by Ultrasound Contrast Agents

Our objective was to investigate whether High‐Intensity Focused Ultrasound (HIFU) hemostasis can be achieved faster in the presence of ultrasound contrast agents (UCA). Incisions (3 cm long and 0.5 cm deep) were made in surgically exposed rabbit liver. Optison at a concentration of 0.18 ml/kg was injected into the mesenteric vein, immediately before the incision was made. The HIFU applicator (frequency of 5.5 MHz, and intensity of 3,700 W/cm2) was scanned manually over the incision (at an approximate rate of 1 mm/s) until hemostasis was achieved. The times to complete hemostasis were measured and normalized with the initial blood loss. The hemostasis times were 59±23 s in the presence of Optison and 70±23 s without Optison. The presence of Optison produced a 37% reduction in the normalized hemostasis times (p<0.05). Optison also provided faster (by 34%) formation of the coagulum seal over the lesion. Gross observations showed that the lesion size did not change due to the presence of Optison. Histological...